A fistula is an abnormal conduit or connection between bodily organs or vessels that do not usually connect. Fistulas or fistulae can form in many parts of the body. Anal fistula and rectal fistula are conditions in which tubes form between a sufferer's rectum and intestines, or other internal organs, or between a sufferer's rectum and the external skin adjacent to the sufferer's anus. For example, fistulas situated high in the anus (high anal fistula) may connect with the urinary tract, and fistulas situated low in the anus (low anal fistula) may, in women, pass into the vagina. In addition to significant pain, rectal and anal fistulas commonly become infected and accumulate pus. Furthermore, such fistulas can allow the leakage of fecal matter from the rectum.
Fistulas may form as a result of disease or infection. For example, anal fistulas may arise if a sufferer's anal glands become blocked, thereby forming an abscess that points through from the rectum to the skin surface in the anal region. The growth of fistulas may be accelerated, and fistulas themselves may be maintained, by a local build up of substances which cause irritation (e.g. in the rectum).
Anal and rectal fistulas may be treated by surgical procedures. Such procedures may be undesirable, however. Surgical procedures are generally relatively expensive compared to medication, and are generally less convenient and less preferable to the patient. Further, a potential side-effect of the surgical procedure to treat fistula is an increased probability that a patient will develop anal incontinence in the years following the surgery.
Activated carbon has been proposed for use in the treatment of rectal and anal fistulas. However, there are a number of problems associated with the use of activated carbon for this purpose. Activated carbon is typically supplied as an extremely fine powder having a high surface area. There are problems associated with handling such a powder because the fine scale of the powder particles means the activated carbon tends to contaminate its immediate surroundings with a fine powder dust of activated carbon.
To alleviate some of the handling problems, activated carbon has previously been prepared for oral administration. However, orally administered activated carbon must pass through part of the patient's digestive system before it reaches the affected area, and in doing so a large (and also unpredictable) proportion of the carbon will have adsorbed various chemicals and lost its activity, or otherwise lost its activity, depending on various factors such as amount of food in gut, inter patient variations and day to day variations. By increasing the dose of orally administered activated carbon it may be possible to increase the proportion of carbon that reaches the rectum in an activated state. However, activated carbon absorbs many essential chemicals and nutrients on passing through the patient's digestive system; the long-term administration of large oral doses of activated carbon over a prolonged period is therefore undesirable.
Activated carbon has also been coated or otherwise formulated to allow it to pass through part of the patient's digestive system when taken orally. For example, U.S. Pat. No. 5,554,370 discloses capsules for oral administration of activated carbon. However, it is difficult to prepare a coating that accurately dissolves to release the activated carbon at the affected area. Furthermore, depending on the materials used, coating or encapsulation may itself reduce or eliminate the activity of the carbon (e.g. the carbon may lose its activity very quickly due to adsorption of components of the coating/formulation by the activated carbon) and thereby may reduce the effectiveness of such coated particles.
European Patent Application No. EP11183665.6, and applications claiming priority therefrom, describe formulations of activated carbon suitable for administering activated carbon as a dry dose.
The present disclosure provides an activated carbon composition for oral administration which retains the adsorptive (pharmaceutical) activity of activated carbon following oral administration until it reaches the site of action (e.g. small or large intestine, anus or rectum), and/or which minimises or avoids adsorption of essential chemicals and nutrients by the activated carbon while the composition passes through the patient's stomach etc. to the site of action.
Thus, according to the present invention there is provided a composition (e.g. a pharmaceutical composition) comprising:
(a) a core comprising activated carbon (e.g. activated carbon as the sole active pharmaceutical ingredient);
(b) a first (e.g. an inner) layer around (e.g. surrounding) the core, the first layer comprising an insoluble semipermeable material; and
(c) a second (e.g. outer) layer around (e.g. surrounding) the first layer which breaks down rapidly (e.g. dissolves) at a predetermined pH (e.g. a layer which breaks down rapidly (dissolves) at pH 5 to pH 7, e.g. a layer which breaks down rapidly (e.g. dissolves) at pH 5, a layer which breaks down rapidly (dissolves) at pH≥15.5, a layer which dissolves at pH 7 etc.). It will be appreciated that the second (e.g. outer) layer around (e.g. surrounding) the first layer which breaks down rapidly (e.g. dissolves) at a predetermined pH does not breaks down rapidly (e.g. dissolve) at other pH (e.g. other pH encountered in the GI tract).
According to the present invention in a further aspect there is provided a composition comprising:
(a) a core comprising activated carbon;
(b) a first layer around the core, the first layer comprising an insoluble semipermeable material; and
(c) a second (e.g. outer) layer around (e.g. surrounding) the first layer which dissolves at a predetermined location in the gastrointestinal tract (e.g. the lower part of the small intestine, the colon etc.).
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
The following discusses the components of the new compositions described herein in more detail.
(b) the First Layer Around the Core, the First Layer Comprising an Insoluble Semipermeable Material:
The first (e.g. an inner) layer may comprise an insoluble semipermeable membrane.
Herein, the term “semipermeable” means that the material (layer) allows (e.g. gradual) diffusion of molecules and ions through the semipermeable material (layer) towards the core and into contact with the activated carbon and/or allows (e.g. gradual) diffusion of selected molecules and ions through the semipermeable material (layer) towards the core and into contact with the activated carbon. The (e.g. selected) molecules and ions may be materials (e.g. toxins or local irritants) which provoke irritation in the gut (e.g. colon and/or rectum). The (e.g. selected) molecules/ions may be molecules/ions which are produced by the body. The (e.g. selected) molecules and ions may be substances which cause, maintain, promote or exacerbate fistula. The first (e.g. an inner) layer may comprise a material (a semipermeable membrane) which allows (e.g. gradual) diffusion of molecules and ions through the semipermeable material (layer) towards the core and into contact with the activated carbon. Preferably, the (insoluble semipermeable) material does not substantially inactivate the activated carbon.
It will be appreciated that the material of the first layer may be selected based on the molecules and/or ions (e.g. substances which cause, maintain, promote or exacerbate fistula) which are to be adsorbed by the activated carbon (and hence removed by excretion).
The first (e.g. inner) layer comprises an insoluble semipermeable material (e.g. a semipermeable membrane). In examples, the insoluble semipermeable material may be, for example, ethyl cellulose; a poly(meth)acrylate polymer such as EUDRAGIT® RL 100, EUDRAGIT® RL PO, EUDRAGIT® RL 30D, EUDRAGIT® RL 12.5, EUDRAGIT® RS 100, EUDRAGIT® RS PO, EUDRAGIT® RS 30D, EUDRAGIT® RS 12.5, EUDRAGIT® NE 30D, EUDRAGIT® NE 40D, all available from Evonik, glycerylmonostearate, cellulose acetate butyrate, dipolylactic acid, polyvinyl chloride. The first (e.g. inner) layer may further comprise a water soluble material (e.g. a water soluble polymer). The water soluble material (e.g. water soluble polymer) may be mixed with the insoluble semipermeable material (e.g. dispersed within the semipermerable material/membrane). In examples, the water soluble material may be, for example sugar, PVA, PVP, hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose, sodium carboxymethyl cellulose, salts, sugar alcohols etc. The water soluble material (e.g. water soluble polymer, e.g. HPMC) may be included in an amount which is 0.1 to 30% by weight of the amount of the insoluble semipermeable material (e.g. ethylcellulose) in the layer (b), for example in an amount which is 2 to 25% by weight of the amount of the insoluble semipermeable material (e.g. ethylcellulose) in the layer (b), for example 5 to 15% by weight of the amount of the insoluble semipermeable material in the layer, for example 10% by weight of the amount of the insoluble semipermeable material in the layer.
The water soluble material (e.g. water soluble polymer, e.g. HPMC) may increase the permeability of the insoluble semipermeable material (e.g. ethyl cellulose). For example, dissolution of the water soluble material e.g. HPMC may form defects or channels in the ethyl cellulose coating, when the first layer is exposed after removal of the second (e.g. enteric) layer (see below), to thereby enable the adsorptive capacity of the activated carbon within the layer. Without being bound by theory, it is believed that the channels allow diffusion of material (e.g. substances which cause, maintain, promote or exacerbate fistula etc.) across the first layer, so it may be adsorbed on the activated carbon. The rate of diffusion may therefore be controlled by the amount of water soluble material (e.g. water soluble polymer, e.g. HPMC), and also the thickness of the film; if the film is thinner, there will be a faster diffusion.
The thickness of the first layer around the core may correspond to a theoretical weight increase (of the core) from the layer (film coating) of 1 to 20%, for example 2 to 10%, for example 3 to 7%, for example 4%. It has been found that a coating of around this thickness provides an effective adsorption capacity.
The first (e.g. inner) layer may consist essentially of the insoluble semipermeable material (e.g. ethyl cellulose) and the water soluble material (e.g. water soluble polymer, e.g. HPMC). Avoiding the use of some other ingredients/excipients in the layer (b) prevents loss of adsorptive capacity of the activated carbon to these excipients.
In other examples, the first (e.g. an inner) layer may comprise a mixture of copolymers composed of 85 to 98% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight (methy) acrylate monomers with a quaternary ammonium group in the alkyl radical. C1- to C4-alkyl esters of acrylic or methacrylic acid are methyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. A preferred (methy) acrylate monomer with a quaternary ammonium group is 2-trimethylammoniummethyl methacrylate chloride.
The first layer may be a copolymer comprising 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride. Such copolymers are commercially available and known as EUDRAGIT® RS type polymers, for example EUDRAGIT® RS 100, EUDRAGIT® RS PO, EUDRAGIT® RS 30D, EUDRAGIT® RS 12.5 etc., available from Evonik Industries. Preferably, the first layer comprises EUDRAGIT® RS 30 D, available from Evonik Industries.
The first (e.g. an inner) layer may comprise a mixture of copolymers composed of 85 to less than 93% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 15 to more than 7% by weight 2-trimethylammoniummethyl methacrylate chloride. The first (e.g. an inner) layer may comprise 50 to 70% by weight methyl methacrylate, and 20 to 40% by weight ethyl acrylate.
The first layer may be a copolymer comprising 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride. Such copolymers are commercially available and known as EUDRAGIT® RL type polymers, for example EUDRAGIT® RL 100, EUDRAGIT® RL PO, EUDRAGIT® RL 30D, EUDRAGIT® RL 12.5 etc., available from Evonik Industries. Preferably, the first layer comprises EUDRAGIT® RL 30 D, available from Evonik Industries.
Preferably, the first (e.g. inner) layer comprises a mixture of a first copolymer comprising 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT® RS) and a second copolymer comprising 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT® RL).
The first layer may be EUDRAGIT® NE 30D or EUDRAGIT® NE 40D, available from Evonik.
The amount of the first (e.g. an inner) layer may be 2 to 20% by weight based on the weight of the core with the activated carbon.
(c) the Second Layer Around the First Layer which Dissolves at a Predetermined PH and/or which Dissolves at a Predetermined Location in the Gastrointestinal Tract:
The second (e.g. outer) layer prevents or reduces exposure of the first layer (and the activated carbon) to the digestive system environment, until a predetermined point in the digestive system after the stomach. The second (e.g. outer) layer may, for example, prevent or reduce exposure of the first layer (and the activated carbon) to the digestive system environment, until the composition reaches the lower part of the intestine, i.e. the late ileum, caecum and/or colon. The second layer may be selected from coatings which are pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria. It will be appreciated that the mechanism of action of the compositions of the present invention (which holds the activated carbon within the inner membrane/layer) is completely opposite to controlled release formulations where an enteric coating is used to protect an inner layer (as it travels through the stomach) but then dissolves in the intestine to expose the inner layer which immediately releases the active pharmaceutical in the lower digestive tract.
The second layer may be a material which remains substantially intact (e.g. is highly stable, e.g. does not disintegrate or dissolve) at (e.g. highly) acidic pH found in the stomach (e.g. pH 1 to 3), but which breaks down rapidly (dissolves) at less acidic (more basic) pH, for example at pH 5 to 7, e.g. pH 5.5. Preferably the second (e.g. outer) layer is a pH sensitive polymer. The second (e.g. outer) layer may be a polymer which breaks down rapidly (dissolves) at a pH of about 5. The second (e.g. outer) layer may be a polymer which breaks down rapidly (dissolves) at a pH of about 7. The amount of second (e.g. outer) layer (e.g. the enteric layer) may be 2 to 35% or even up to 50% w/w of the total composition, for example the amount of second (e.g. outer) layer (e.g. the enteric layer) may be 8 to 16% w/w of the total composition, for example 10 to 14% w/w of the total composition, for example 12% w/w of the total composition.
The thickness of the second (e.g. outer) layer (e.g. the enteric layer) around the core may correspond to a theoretical weight increase (of the core and first layer) from the film coating of 4 to 16%, for example 6% to 14%, for example 8% or 12%. It was found (see tests below) that such a coating should ensure passage of the stomach prior to exposure of the first layer.
Preferably the second (e.g. outer layer) is an enteric layer. The enteric layer (enteric coating layer) prevents or reduces exposure of the first layer (and the activated carbon) to the digestive system environment, until the composition reaches the small intestine (and even after the composition reaches the small intestine the semipermeable membrane may minimise or prevent adsorption of beneficial substances such as nutrients by the activated carbon).
In some preferred examples, the layer(s) are chosen so the first (inner) layer is exposed in the small intestine, preferably close to the colon (to minimise adsorption of beneficial substances and reserve the bulk of the adsorptive capacity until the colon is reached). Preferably, the enteric layer is a material which remains substantially intact (is highly stable) at (e.g. highly) acidic pH found in the stomach (e.g. pH 1 to 3), but which breaks down rapidly (dissolves) at less acidic (more basic) pH, for example at pH 5 to 7, e.g. pH≥5.5, for example pH 7 as found in small intestine. Preferably the enteric layer (enteric coating layer) is a pH sensitive polymer. The pH sensitive polymer may have a free acid group (carboxylic acid group) with dissolution caused by deprotonation of the acid group. The enteric layer (enteric coating layer) may be a polymer which breaks down rapidly (dissolves) at a pH of about 5. The enteric layer (enteric coating layer) may be a polymer which breaks down rapidly (dissolves) at a pH of about 7. The enteric layer (enteric coating layer) may be a water soluble polymer. The enteric layer may comprise one or more of a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, sodium alginate and stearic acid. The enteric layer may be a fatty acid, wax, shellac, plastics material etc. The enteric layer may be a pH-dependent enterosoluble polymers, such as cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylic acid and ethyl acrylate copolymers, methacrylic acid and ethyl acrylate copolymers, methacrylic acid and methyl methacrylate copolymers (1:1 ratio), methacrylic acid and methyl methacrylate copolymers (1:2 ratio), Polyvinyl acetate phthalate (PVAP) and Shellac resins. The enteric layer may be EUDRAGIT® E100, E12.5 or E PO. The enteric layer may be, for example, EUDRAGIT® L 100, EUDRAGIT® L 30D, a mixture of EUDRAGIT® S 100/FS 30 D and EUDRAGIT® L 100 (see below). These EUDRAGIT® products are available from Evonik Industries.
The enteric layer may comprise hydroxypropylmethylcellulose acetate succinate (HPMC AS), for example a HMPC AS which dissolves at pH between 5.5 to 6.8. As is known in the art, it is possible to vary the content of acetate and succinate in HPMC AS to provide an enteric coating which dissolves from pH>5.5 to pH>6.8. The enteric layer may consist of, or consist essentially of, hydroxypropylmethylcellulose acetate succinate (HPMC AS), for example a HMPC AS which dissolves at pH between 5.5 to 6.8.
The amount of enteric layer may be 2 to 35% or even up to 50% w/w of the total composition, for example the amount of the enteric layer may be 8 to 16% w/w of the total composition, for example 10 to 14% w/w of the total composition, for example 12% w/w of the total composition.
The thickness of the second (e.g. outer) layer (e.g. the enteric layer) around the core may correspond to a theoretical weight increase (of the core and first layer) from the film coating of 4 to 16%, for example 6% to 14%, for example 8% or 12%. It was found from tests below that such a coating should ensure passage of the stomach prior to exposure of the first layer.
The enteric layer (enteric coating layer) may comprise a copolymer composed of 80 to 95% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 5 to 25% by weight (meth)acrylate monomers with an anionic group in the alkyl radical. C1- to C4-alkyl esters of acrylic or methacrylic acid are methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate.
A (meth)acrylate monomer with an anionic group in the alkyl radical may be, for example, acrylic acid or methacrylic acid.
The enteric layer may be a (meth)acrylate copolymer comprising 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid. Such polymers are commercially available and known as EUDRAGIT® FS type polymers. Preferably, the enteric layer comprises EUDRAGIT® FS 30 D, available from Evonik Industries.
The enteric layer may be EUDRAGIT® E100, E12.5 or E PO. The enteric layer may be, for example, EUDRAGIT® L 100, EUDRAGIT® L 30D, a mixture of EUDRAGIT® S 100/FS 30 D and EUDRAGIT® L 100 (see below). These EUDRAGIT® products are available from Evonik Industries.
The amount of the second (enteric) layer may be 5 to 15% by weight based on the weight of the core with the activated carbon and the inner layer.
Preferably the composition or pharmaceutical composition is for oral administration (is orally administrable). The (pharmaceutical) composition may be for (use in) the treatment of gastrointestinal (GI) dysfunction and/or diseases or malfunction of the GI tract or the like, for example fistula [for example gastrointestinal fistula (e.g. fistula of the lower part of the small intestine, fistula of the large intestine, anorectal fistula)], Irritable Bowel disease, IBD [Ulcerative Colitis or Crohn's disease, Irritable Bowel Syndrome (IBS)]; or for use in the treatment of poisoning (e.g. alcohol poisoning); or for use in reducing or eliminating the side effects of pharmaceutical compositions which are caused when these pharmaceutical compositions or their metabolites (e.g. antibiotics, irinotecan or its metabolite SN38 etc.) are present or build up in the lower ileum, colon or caecum.
Preferably the composition (e.g. pharmaceutical composition) is for, or for use in, the treatment of fistula, for example gastrointestinal fistula (e.g. fistula of the small intestine, fistula of the large intestine, anorectal fistula). The composition (e.g. pharmaceutical composition) may be for use in the manufacture of a medicament for the treatment of fistula, for example gastrointestinal fistula (e.g. fistula of the lower part of the small intestine, fistula of the large intestine, anorectal fistula).
While not being limited by any theory, it will be appreciated that examples of the invention may work as follows. The outer (e.g. enteric) layer of the composition remains substantially intact at the acidic pH found in the stomach (e.g. pH 1 to 3), and the pharmaceutical composition therefore remains substantially intact as it travels to and through the stomach following oral administration. However, the outer (e.g. enteric) layer breaks down and dissolves at the pH found in the small intestine (e.g. pH 5 found in the upper part of the small intestine, or pH 7 found in the lower part of the small intestine), thereby exposing the first (e.g. inner) layer. It should be noted that even after the composition reaches the small intestine (and the enteric layer dissolves) the semipermeable membrane (in the first layer) may minimise adsorption of beneficial substances such as nutrients by the activated carbon. In some preferred examples, the layer(s) are chosen so the first (inner) layer is exposed in the lower part of the small intestine, preferably close to the colon (to minimise adsorption of beneficial substances and save the bulk of the adsorptive capacity for the colon). The first layer comprises a material (e.g. a semipermeable membrane) which may allow gradual diffusion of molecules and ions (e.g. materials which irritate the colon or rectum, substances which cause, maintain, promote or exacerbate fistula, etc.) through the semipermeable membrane towards the core into contact with the activated carbon, where they are adsorbed. In some examples, dissolution of a water soluble material (e.g. HPMC) in the semipermeable material (e.g. ethyl cellulose) may form defects or channels in the semipermeable material/layer, when the first (e.g. inner) layer is exposed after removal of the second (e.g. enteric) layer, to thereby slowly enable the adsorptive capacity of the activated carbon within the layer. The (insoluble semipermeable) material does not substantially inactivate the activated carbon, so the activated carbon is available to adsorb these molecules/ions. It will be appreciated that substantially all of the activated carbon is held (remains) within the semipermeable membrane as the composition (minus the outer layer) travels on through the digestive system (e.g. through the lower part of the small intestine and the colon); the activated carbon is not released and is therefore less able to remove (adsorb) essential chemicals such as nutrients.
It will be appreciated that inclusion of the semipermeable membrane (the first, inner, layer) may enable the adsorptive capacity of the activated carbon to be maintained as the composition travels through the whole large intestine [and the formulations may even retain some adsorptive capacity even as they pass through the rectum and anus (i.e. the compositions of the invention may still have adsorptive capacity while they are in the rectum or anus)]. If the semipermeable membrane/first layer were not present the removal of the outer (enteric) layer would make all of the adsorptive capacity of the activated carbon available at once (e.g. at the top of the small intestine), and the amount of adsorptive activity remaining available by the time the composition reached the large intestine may be insufficient to treat the medical condition.
Without wishing to be bound by theory, it is believed that molecules (e.g. toxins or irritants, e.g. substances which cause, maintain, promote or exacerbate fistula) are able to diffuse through the semipermeable membrane where they are adsorbed by the activated carbon and then held on the carbon and subsequently removed by excretion. It will be appreciated that the mechanism of action of the compositions of the present invention (which holds the activated carbon within the inner membrane/layer) is completely opposite to controlled release formulations where an enteric coating is used to protect an inner layer (as it travels through the stomach) but then dissolves in the intestine to expose the inner layer which immediately releases the active pharmaceutical in the lower digestive tract.
The applicants have found that the compositions of the invention may provide a more constant adsorption as they proceed through the gut (after removal of the enteric layer). The retention of adsorptive capacity of activated carbon through the gut (even, depending on the coating used, until the rectum or anus) is important because the exact location of the fistula may not be known and/or because it may be difficult to target the exact site of the fistula.
(a) A Core Comprising Activated Carbon
The core comprises activated carbon. Preferably the core consists of, or consists essentially of, activated carbon. In other words, it is preferred that the core is 100% activated carbon (i.e. activated carbon alone, without other excipients or active ingredients). Thus, preferably the core does not include carrageenan (or a granulation enhancer etc.). The applicants have surprisingly found that it is possible to work with and coat individual granules of activated carbon (e.g. of specific size and/or hardness) without requirement for a granulation excipients such as carrageenan.
The activated carbon is preferably sanded or deburred. Herein, the term “deburred” means untreated “raw” activated carbon is subjected to a finishing process to reduce or minimise the number of tips, peaks and edges (from the surface). The activated carbon may be deburred by the process described below. The active carbon may be deburred or sanded by causing the untreated activated carbon particles to collide with each other at high speed (e.g. speeds from 30 to 300 km/h, for example 35 to 70 km/h). The burred or sanded activated carbon (of specific size) may then be separated for use in/as core (a).
The activated carbon may include 0.9 or fewer tips peaks and edges of height 20-100 μm per particle or granule, for example 0.8 tips or fewer peaks and edges per particle/granule, for example 0.6 tips peaks and edges or fewer per particle/granule, when measured using the microscopy and digital image analysis technique described below.
The activated carbon may be, for example, of particle size 0.02 to 5 mm (depending on the raw material from which the activated carbon is made). The activated carbon may be, for example, of particle size 0.02 to 2.1 mm, for example 0.05 to 2.1 mm, for example 0.1 to 2 mm, for example 0.2 to 2 mm. The activated carbon may be of particle size from 0.6 to 1.2 mm. The activated carbon of this particle size may be selected by sieving the activated carbon (e.g. after it has been sanded/deburred); by selecting activated carbon which includes particles that will pass through a 1.2 mm sieve (i.e. a sieve having aperture size 1.2 mm) but will not pass through a 0.6 mm sieve. Preferably the activated carbon is of particle size from 0.6 to 1.0 mm. The activated carbon of this particle size may be selected by sieving activated carbon (e.g. after it has been sanded/deburred); the preferred activated carbon includes particles that will pass through a 1.0 mm sieve (i.e. a sieve having aperture size 1.0 mm) but will not pass through a 0.6 mm sieve. Herein the term “particle size” means the width at the narrowest point of the activated carbon particle or granule (e.g the diameter for a spherical or roughly spherical particle).
The activated carbon may be made from coconut shells.
Activated carbon (e.g. granular activated carbon) and its methods of manufacture is well known in the art and is available from, for example, Chemviron Carbon.
The applicants have found that activated carbon of particle size between 0.6 to 1.2 mm (e.g. 0.6 to 1.0 mm) and/or which has been sanded or deburred is ready to process (i.e. coat with the first layer); there is no need to granulate/process/extrude/spheronise the carbon or add a granulating agent such as carrageenan. This simplifies the process and means that each core has very high absorption capacity (the core is all activated carbon and there are no excipients etc. present to “dilute” the adsorption capacity). Further, the deburring has the effect of stabilising the adsorbtion rate. Sanding or deburring the raw activated carbon reduces the number of edges (per gram) on the surface of the activated carbon. The raw material is itself very hard to coat consistently, due to the roughness. If the particle is rough, there is high variation in coating thickness over the surface of the overall particle, which has an effect on coating homogeneity and resulting exposure of adsorptive capacity prematurely (e.g. before the colon). Smoothing the activated carbon by sanding or deburring the surface means that the coating thickness is more consistent: the adsorptive capacity of activated carbon is provided in the appropriate place (e.g. in the colon)
The activated carbon may be granular activated carbon. Preferably the core is a granule of activated carbon. It is preferred that the activated carbon particles/granules are formed by grinding or milling carbon material to the desired size. Ground activated carbon has an irregular particle shape. The activated carbon may be in the form of spheronised or spherical particles. The activated carbon may be coated. The activated carbon may be a pharmaceutical or medical grade activated carbon (e.g. activated carbon which complies with Ph. Eur., apart from the particle size).
Preferably the activated carbon is made from coconut shells.
It is preferred that the activated carbon is the sole active pharmaceutical ingredient. Further, it is preferred that the core does not include carrageenan.
The (e.g. pharmaceutical) compositions of the invention may be, may be for use as, or may be for use in the manufacture of, a pharmaceutical formulation or preparation. The pharmaceutical formulation or preparation may, for example, be for, or for use in, the treatment of gastrointestinal (GI) dysfunction and/or diseases or malfunction of the GI tract or the like, for example fistula [for example gastrointestinal fistula (e.g. fistula of the lower part of the small intestine, fistula of the large intestine, anorectal fistula)], Irritable Bowel disease, IBD [Ulcerative Colitis or Crohn's disease, Irritable Bowel Syndrome (IBS)]; the pharmaceutical formulation or preparation may be for, or for use in, the treatment of poisoning (e.g. alcohol poisoning); the pharmaceutical formulation or preparation may be for, or for use in, reducing or eliminating the side effects of pharmaceutical compositions which are caused when these pharmaceutical compositions or their metabolites (e.g. antibiotics, irinotecan or its metabolite SN38 etc.) are present or build up in the lower ileum, colon or caecum.
The (e.g. pharmaceutical) compositions may be used to treat patients who are also receiving activated carbon administered rectally.
According to the present invention in a further aspect there is provided a pharmaceutical formulation or preparation comprising one or more (e.g. a plurality) of compositions according to any aspect of the invention. The pharmaceutical formulation or preparation may comprise one, or generally very many more, compositions according to the invention, each comprising a core (e.g. granule of activated carbon), inner layer and outer layer. In this example the pharmaceutical formulation or preparation (which may comprise tens or hundreds of such compositions) may be administered as a powder or granules, as a microparticulate formulation, or suspended in a pharmaceutically acceptable solution. The pharmaceutical formulation or preparation may comprise one or more compositions [each comprising a core (e.g. granule of activated carbon), inner layer and outer layer] e.g. which are formulated in a dosage form, e.g. an oral dosage form, e.g. a tablet or capsule. In an example, a pharmaceutical formulation or preparation is in the form of a capsule which includes 400 mg of the composition(s) of the invention. The pharmaceutical formulation or preparation may comprise additional components such as dryers (such as alumina, aerosils etc.), release agents, stabilizers, colourants, antioxidants, wetting agents, pigments, gloss agents, plasticisers, disintegrants etc. The use of these agents (and the amount required) is well known and customary in the art.
According to the present invention a composition (e.g. a pharmaceutical composition) comprises:
(a) a core comprising activated carbon (e.g. activated carbon as the sole active pharmaceutical ingredient, e.g. sanded/deburred activated carbon, e.g. activated carbon of particle size 0.6 to 1.0 mm);
(b) a first (e.g. an inner) layer around (e.g. surrounding) the core, the first layer comprising an insoluble semipermeable material in the form of ethyl cellulose, and optionally further comprising a water soluble material in the form of hydroxypropylmethylcellulose (HPMC);
(c) a second (e.g. outer) layer comprising hydroxypropylmethylcellulose acetate succinate (HPMC AS).
In an example, the composition (pharmaceutical composition) comprises:
a) a core comprising (e.g. which is) activated carbon;
b) an inner layer (coating) of a copolymer or of a mixture of copolymers composed of 85 to 98% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight (methy) acrylate monomers with a quaternary ammonium group in the alkyl radical; and
c) an outer layer (coating) of a copolymer composed of 80 to 95% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 5 to 25% by weight (meth)acrylate monomers with an anionic group in the alkyl radical.
The composition (pharmaceutical composition) may comprise:
a) a core comprising (e.g. which is) activated carbon;
(b) an inner layer (coating) comprising a mixture of a first copolymer comprising 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT® RS, e.g. EUDRAGIT® RS 30D) and a second copolymer comprising 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT® RL, e.g. EUDRAGIT® RL 30D); and
(c) an outer (enteric) layer (coating) comprising a (meth)acrylate copolymer comprising 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid (EUDRAGIT® FS, e.g. EUDRAGIT® FS 30 D).
Preferably the core is activated carbon. In other words, it is preferred that the core is 100% activated carbon (i.e. activated carbon alone, without other excipients or active ingredients). The core may be a granule of activated carbon. The compositions of the invention may further comprise additional components such as dryers (such as alumina, aerosils etc.), release agents, stabilizers, colourants, antioxidants, wetting agents, pigments, gloss agents, plasticisers etc. The use of these agents (and the amount required) is well known and customary in the art.
The pharmaceutical compositions described herein may be used for the treatment of a gastrointestinal (GI) dysfunction and/or diseases or malfunction of the GI tract or the like, for example fistula [for example gastrointestinal fistula (e.g. fistula of the lower part of the small intestine, fistula of the large intestine, anorectal fistula], Irritable Bowel disease, IBD [Ulcerative Colitis or Crohn's disease, Irritable Bowel Syndrome (IBS)]; for the treatment of poisoning (e.g. alcohol poisoning); or for treatment to reduce or eliminate the side effects of pharmaceutical compositions which are caused when these pharmaceutical compositions or their metabolites (e.g. antibiotics, irinotecan or itrs metabolite SN38 etc.) are present or build up in the lower ileum, colon or caecum. The methods of treatment include administering (e.g. orally) to a patient in need thereof a (pharmaceutically effective amount of a) composition (e.g. a pharmaceutical composition) as described herein.
According to the present invention in a further aspect there is provided a method of treatment of gastrointestinal (GI) dysfunction and/or diseases or malfunction of the GI tract or the like, for example fistula [for example gastrointestinal fistula (e.g. fistula of the lower part of the small intestine, fistula of the large intestine, anorectal fistula)]. Irritable Bowel disease, IBD [Ulcerative Colitis or Crohn's disease, Irritable Bowel Syndrome (IBS)]; a method of treatment of poisoning (e.g. alcohol poisoning); or a method of treatment to reduce or eliminate the side effects of pharmaceutical compositions which are caused when these pharmaceutical compositions or their metabolites (e.g. antibiotics, irinotecan or its metabolite SN38 etc.) are present or build up in the lower ileum, colon or caecum; the method, comprising a step of administering (e.g. orally) to a patient in need thereof a (pharmaceutically effective amount of a) composition (e.g. a pharmaceutical composition) comprising:
(a) a core comprising activated carbon (e.g. activated carbon as the sole active pharmaceutical ingredient);
(b) a first (e.g. an inner) layer around (e.g. surrounding) the core, the first layer comprising an insoluble semipermeable material; and
(c) a second (e.g. outer) layer around (e.g. surrounding) the first layer which breaks down rapidly (dissolves) at a predetermined pH (e.g. a layer which breaks down rapidly (dissolves) at pH 5 to pH7, e.g. a layer which breaks down rapidly (dissolves) at pH 5, a layer which breaks down rapidly (dissolves) at pH≥5.5, a layer which dissolves at pH 7 etc.) and/or which dissolves at a predetermined location in the gastrointestinal tract.
Preferably the core is activated carbon. In other words, it is preferred that the core is 100% activated carbon (i.e. activated carbon alone, without other excipients or active ingredients). The core may be a granule of activated carbon.
The treatment may comprise administration of an effective dose of activated carbon of 50 mg to 10 g activated carbon, for example 100 mg to 5 g activated carbon, for example 100 mg to 4 g activated carbon. The treatment may comprise administration of a total dose of 50 mg to 10 g activated carbon, for example 100 mg to 5 g activated carbon, for example 100 mg to 4 g (e.g. 3.2 g) activated carbon, per day. The total dose may be administered in a single dose, or may be divided into more than one dose, per day. The skilled person would readily understand, based on the weight of the composition and the weight of activated carbon therein, the amount of the composition (which of course includes a certain amount of other components) required to achieve these effective doses.
The fistula may be, e.g. gastrointestinal fistula (e.g. fistula of the small intestine, fistula of the large intestine, anorectal fistula).
The method may comprise a step of administering (e.g. orally) a composition (pharmaceutical composition) comprising:
a) a core comprising activated carbon;
b) an inner layer of a copolymer or of a mixture of copolymers composed of 85 to 98% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight (methy) acrylate monomers with a quaternary ammonium group in the alkyl radical; and
c) an outer layer of a copolymer composed of 80 to 95% by weight free-radical polymerized C1- to C4-alkyl esters of acrylic or methacrylic acid and 5 to 25% by weight (meth)acrylate monomers with an anionic group in the alkyl radical.
The method may comprise a step of administering (e.g. orally) a composition (pharmaceutical composition) comprising:
a) a core comprising activated carbon;
(b) an inner layer comprising a mixture of a first copolymer comprising 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT® RS, e.g. EUDRAGIT® RS 30D) and a second copolymer comprising 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT® RL, e.g. EUDRAGIT® RL 30D); and
(c) an outer (enteric) layer comprising a (meth)acrylate copolymer comprising 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid (EUDRAGIT® FS, e.g. EUDRAGIT® FS 30 D).
Preferably the core is activated carbon. In other words, it is preferred that the core is 100% activated carbon (i.e. activated carbon alone, without other excipients or active ingredients). The core may be a granule of activated carbon. The composition may be administered as a powder, granules, suspension, tablet, capsule etc.
According to the present invention in a further aspect there is provided a method of treatment of gastrointestinal (GI) dysfunction and/or diseases or malfunction of the GI tract or the like, for example fistula [for example gastrointestinal fistula (e.g. fistula of the lower part of the small intestine, fistula of the large intestine, anorectal fistula)], Irritable Bowel disease, IBD [Ulcerative Colitis or Crohn's disease, Irritable Bowel Syndrome (IBS)]; a method of treatment of poisoning (e.g. alcohol poisoning); or a method of treatment to reduce or eliminate the side effects of pharmaceutical compositions which are caused when these pharmaceutical compositions or their metabolites (e.g. antibiotics, irinotecan or its metabolite SN38 etc.) are present or build up in the lower ileum, colon or caecum; the method, comprising a step of administering (e.g. orally) to a patient in need thereof a composition (e.g. a pharmaceutical composition) comprising:
(a) a core comprising activated carbon (e.g. activated carbon as the sole active pharmaceutical ingredient, e.g. sanded/deburred activated carbon, e.g. activated carbon of particle size 0.6 to 1.0 mm);
(b) a first (e.g. an inner) layer around (e.g. surrounding) the core, the first layer comprising an insoluble semipermeable material in the form of ethyl cellulose, and optionally further comprising a water soluble material in the form of hydroxypropylmethylcellulose (HPMC);
(c) a second (e.g. outer) layer comprising hydroxypropylmethylcellulose acetate succinate (HPMC AS).
The fistula may be, e.g. gastrointestinal fistula (e.g. fistula of the small intestine, fistula of the large intestine, anorectal fistula). The treatment may comprise administration of an effective dose of activated carbon of 50 mg to 10 g activated carbon, for example 100 mg to 5 g activated carbon, for example 100 mg to 4 g activated carbon. The treatment may comprise administration of a total dose of 50 mg to 10 g activated carbon, for example 100 mg to 5 g activated carbon, for example 100 mg to 4 g (e.g. 3.2 g) activated carbon, per day. The total dose may be administered in a single dose, or may be divided into more than one dose, per day. The skilled person would readily understand, based on the weight of the composition and the weight of activated carbon therein, the amount of the composition (which of course includes a certain amount of other components) required to achieve these effective doses.